Abstract
Endurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact across species. While endurance exercise supports neural plasticity, enhanced memory, and reduced neurodegeneration, less is known about the effect of chronic exercise on the progression of movement disorders such as ataxias. Here, we focused on three different types of ataxias, spinocerebellar ataxias type (SCAs) 2, 3, and 6, belonging to the polyglutamine (polyQ) family of neurodegenerative disorders. In Drosophila models of these SCAs, flies progressively lose motor function. In this study, we observe marked protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 models, with no benefit to SCA3 flies. Causative protein levels are reduced in SCA2 flies after chronic exercise, but not in SCA3 models, linking protein levels to exercise-based benefits. Further mechanistic investigation indicates that the exercise-inducible protein, Sestrin (Sesn), suppresses mobility decline and improves early death in SCA2 flies, even without exercise, coincident with disease protein level reduction and increased autophagic flux. These improvements partially depend on previously established functions of Sesn that reduce oxidative damage and modulate mTOR activity. Our study suggests differential responses of polyQ SCAs to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration. Defining the mechanisms by which endurance exercise suppresses polyQ SCAs will open the door for more effective treatment for these diseases.
Highlights
Nine inherited neurodegenerative disorders are caused by expansion of a CAG triplet repeat in the protein-coding region of the respective disease genes
To test if endurance exercise reduces polyQ-dependent phenotypes in the fly, we selected three Spinocerebellar Ataxias Type (SCAs): Figure 1: Endurance exercise differentially affects mobility in Drosophila models of Spinocerebellar Ataxia. (A) Spinocerebellar Ataxia (SCA) models used in this study
We examined disease protein levels in sqh>ATXN2Q117;dSesnWT;ATXN2Q117 flies and found significant reduction in ATXN2 compared to SCA2 flies without dSesn expression (Figure 4C, F, quantified in Figure 7), similar to aforementioned reduction in disease protein after exercise
Summary
Nine inherited neurodegenerative disorders are caused by expansion of a CAG triplet repeat in the protein-coding region of the respective disease genes. The CAG repeat encodes the amino acid glutamine; the disease protein carries a lengthened tract of polyglutamine (polyQ) residues that renders it toxic. Various pathogenic mechanisms are shared, involving primarily toxic gain-of-function acquired by the disease protein. These mutations yield aggregation of the toxic polyQ protein and, despite their wide expression throughout the body, only select central nervous system regions degenerate in each disease. The disorders share disease mechanisms, the individual host proteins have divergent functions [1,2,3,4,5,6,7]
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